Even though ethanol itself is not genotoxic or carcinogenic in test systems, in epidemiological studies it has been found to increase greatly the risk of certain human cancers, especially in synergism with tobacco use. One hypothesis is that it potentiates the effects of genotoxic environmental agents, such as the nitrosamines found in tobacco, by inhibiting clearance in liver and increasing exposure of other organs. In further tests of this hypothesis, we quantified the inhibitory effect of ethanol on metabolism of N-nitrosodimethylamine (NDMA) in strain A and Swiss mice. In Swiss mice, an i.g. ethanol dose preceding NMDA i.g. resulted in up to 450-fold increases in AUC, mean residence times, and clearance half-times. In strain A mice, increases in lung NDMA concentrations were more than sufficient to account for previously observed increases in DNA adducts and tumors in lungs of similarly-treated mice. Effects of ethanol were also tested with regard to tumorigenesis by several other low molecular weight nitrosamines known or likely to occur in the environment. Inclusion of ethanol with N-nitroso-diethylamine in the drinking water resulted in 4-fold and 16-fold enhancements of numbers of lung tumors and forestomach tumors, respectively. Given with N-nitrosopyrrolidine, ethanol caused a 5.5-fold increase in lung tumor multiplicity. Inclusion of ethanol with N6-(methylnitroso)adenosine led to shortened survival time related to hemangiosarcoma occurrence or increased incidence of thymic lymphomas, depending on dose of carcinogen. In sum the results of these studies provide further strong evidence, with both toxicokinetic and tumorigenic endpoints, in support of the idea that ethanol potentiates tumorigenesis by nitrosamines by a mechanism involving inhibition of first-pass clearance. Future studies will expand the focus on a second "special carcinogenesis model," foreign body oncogenesis, in the context of risks posed by mammaplasty devices and other permanent tissue implants (cf. project Z01CP05301).